Mutation of TBCK causes a rare recessive developmental disorder

Abstract

Objective: To characterize the underlying genetic defect in a family with 3 siblings affected by a severe, yet viable, congenital disorder.

Methods: Extensive genetic and metabolic investigations were performed, and the affected children were imaged at different ages. Whole-genome genotyping and whole-exome sequencing were undertaken. A single large region (>8 Mb) of homozygosity in chromosome 4 (chr4:100,268,553-108,609,628) was identified that was shared only in affected siblings. Inspection of genetic variability within this region led to the identification of a novel mutation. Sanger sequencing confirmed segregation of the mutation with disease.

Results: All affected siblings share homozygosity for a novel 4-bp deletion in the gene TBCK (NM_033115:c.614_617del:p.205_206del).

Conclusions: This finding provides the genetic cause of a severe inherited disease in a family and extends the number of mutations and phenotypes associated with this recently identified disease gene.

Figure 1. Pedigree of the family studied, photographs, and identification of a homozygous mutation in TBCK

(A) Pedigree showing complete segregation of the TBCK c.614_617del; p.205_206del mutation in the family members available for analysis. (B) Photographs of the affected siblings. (C) Sanger sequencing traces for all family members available for analysis (2 affected siblings, the parents, and 1 unaffected sibling). The 3 upper chromatograms represent a reference sequence and the unaffected family members where the heterozygous deletion can be observed. The 2 lower chromatograms represent 2 of the affected siblings where the same deletion can be observed in homozygosity.